Abstract: The Trial to Reduce Insulin Dependent Diabetes in the Genetically at Risk ('TRIGR') will determine whether weaning to a formula in which (foreign) proteins have been extensively hydrolysed, reduces disease risk for Type 1 Diabetes (T1D) in genetically susceptible children, as it does in rodent models. The Specific Aims are: I-a: To determine whether weaning to a hydrolysed casein formula (Nutramigen") reduces the frequency of diabetes-predictive autoantibodies, and I-b: To determine whether weaning to casein hydrolysate reduces the frequency of clinical diabetes. This double blind, randomized controlled trial in subjects with an affected first degree relative and risk-associated HLA genotypes is currently in its 9th year. An international, multicenter consortium has been developed comprising 77 centers in 15 countries. Enrollment of 2160 eligible infants was completed successfully, providing a cushion above the required 2032 infants. The 6-8 month intervention designed to compare the effects of either hydrolysed casein or standard cow milk based weaning formula was completed in 2007. Duration of breast feeding at the mothers'discretion was similar to or above background populations All subjects are followed during and after the intervention period for at least 10 years with measurements of serological markers of intact cow milk exposure, diabetes predictive autoantibodies (the end point at age 6 years) and the clinical and/or metabolic indices of diabetes (the end point at age 10 years). Currently all planning parameters have been met and drop out rates are <2% with compliance at expected levels. A large, cross-linked repository of stored sera, DNA T-cell data and and cryopreserved peripheral blood mononuclear cells allow independently funded ancillary and mechanistic studies related to the natural history of prediabetes and the hypothesis to be tested. This application covers years 11- 15 for the US coordinating and clinical centers for this 17 year study which is submitted in tandem with those of the European coordinating center and clinical centers and that of the Data Management Unit. PUBLIC HEALTH RELEVANCE: Relevance: Cow milk protein is the most common intact foreign weaning protein in humans. If our intervention is effective in delaying autoimmunity or ultimately its progression to clinical diabetes, this first ever primary prevention study of T1D, will have far-reaching impact for individuals and the global society.